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The juxtamembrane linker of synaptotagmin 1 regulates Ca2+ binding via liquid-liquid phase separation

Author

Listed:
  • Nikunj Mehta

    (University of Wisconsin−Madison)

  • Sayantan Mondal

    (Boston University)

  • Emma T. Watson

    (University of Wisconsin−Madison)

  • Qiang Cui

    (Boston University)

  • Edwin R. Chapman

    (University of Wisconsin−Madison)

Abstract

Synaptotagmin (syt) 1, a Ca2+ sensor for synaptic vesicle exocytosis, functions in vivo as a multimer. Syt1 senses Ca2+ via tandem C2-domains that are connected to a single transmembrane domain via a juxtamembrane linker. Here, we show that this linker segment harbors a lysine-rich, intrinsically disordered region that is necessary and sufficient to mediate liquid-liquid phase separation (LLPS). Interestingly, condensate formation negatively regulates the Ca2+-sensitivity of syt1. Moreover, Ca2+ and anionic phospholipids facilitate the observed phase separation, and increases in [Ca2+]i promote the fusion of syt1 droplets in living cells. Together, these observations suggest a condensate-mediated feedback loop that serves to fine-tune the ability of syt1 to trigger release, via alterations in Ca2+ binding activity and potentially through the impact of LLPS on membrane curvature during fusion reactions. In summary, the juxtamembrane linker of syt1 emerges as a regulator of syt1 function by driving self-association via LLPS.

Suggested Citation

  • Nikunj Mehta & Sayantan Mondal & Emma T. Watson & Qiang Cui & Edwin R. Chapman, 2024. "The juxtamembrane linker of synaptotagmin 1 regulates Ca2+ binding via liquid-liquid phase separation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44414-5
    DOI: 10.1038/s41467-023-44414-5
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    2. Hua Bai & Renhao Xue & Huan Bao & Leili Zhang & Arun Yethiraj & Qiang Cui & Edwin R. Chapman, 2016. "Different states of synaptotagmin regulate evoked versus spontaneous release," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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